The book details the brutal 1959 murders of Herbert Clutter, a wealthy farmer from Holcomb, Kansas, and his wife and two of their children. When Capote learned of the quadruple murder before the killers were captured, he decided to travel to Kansas and write about the crime. Bringing his childhood friend and fellow author Harper Lee along, together they interviewed local residents and investigators assigned to the case and took thousands of pages of notes. The killers, Richard "Dick" Hickock and Perry Smith, were arrested not long after the murders, and Capote ultimately spent six years working on the book. It is considered the originator of the non-fiction novel and the forerunner of the New Journalism movement, although other writers, like Rodolfo Walsh, had already explored the genre in books like Operación Masacre.

The plot weaves a complicated psychological story of two parolees who together commit a mass murder, an act they were not capable of individually. Capote's book also details the lives of the victims and the effect the crime had on the community where they lived. A large part of the story involves the dynamic psychological relationship of the two felons that culminated in this senseless crime. In Cold Blood is often regarded by critics as a pioneering work of true crime.